The existing technology discloses that glucocorticoid drugs provide remarkable anti-inflammatory effect, immunosuppressive effect and antishock effect, thus they are widely applied to clinical diseases therapy. Glucocorticoid drugs are also most commonly used drugs applied on treating diseases of respiratory system, such as bronchial asthma, chronic obstructive pulmonary disease, interstitial lung disease, acute lung injury (ALI), pulmonary vasculitis, acute respiratory distress syndrome (ARDS) and so on. Wherein, treatment of some diseases such as bronchial asthma, sarcoidosis need long-term administration of the hormone. However, glucocorticoid drugs are medicine with quite obvious adverse drug reaction, which often results in a series of side effects, for example, anaphylactic reaction, hyperglycemia, hypertension, peptic ulcer, gastrointestinal bleeding, osteoporosis, Cushing syndrome, which may make patients physically disabled or even be life-threatening in severe patients. Therefore, it is an important issue which must be solved on the clinical and basic research that how to reduce glucocorticoid drugs concentration in non-treated areas to avoid adverse drug reaction for maximizing therapeutic effect.
In recent years, the rapid development of targeting nanotechnology brings new hope to solve the medical problem. Nanotechnology has been successfully applied in many technical fields, wherein, nano-drug delivery system based on the nanotechnology becomes one of the major developmental tendencies of modern medicine. Compared to ordinary dosage forms, the nanostructure of medicine provides bigger specific surface area, higher chemical activity and faster absorption rate, prolongs therapeutic drug level, lowers the risk of adverse drug reaction and improves medicine curative effect. On research of setting the target activity of medicine, nano-drug carrier with targeting becomes a research focus on nanotechnology and medicine controlled-release technique. The nano-drug carrier with targeting has characteristics of controlling drug release according to physical and psychological needs so as to form a drug delivery system in nanoscale. Based on different stimulus signals, the drug delivery system can be classified as a physical signal stimuli responsive drug delivery system, a chemical signal stimuli responsive drug delivery system and a biological signal stimuli responsive drug delivery system. Biological target therapy comprises: as utilization of antibody, with the help of specificity effect of cell membrane surface receptor or particular gene segment, the ligand is bonded to the carrier, then it is specifically bonded to an antigenicity recognizer on the surface of the target cell by the action of the promoter, so that the drugs are delivered to target cells precisely, for implementing target therapy.
In 1993, Hamers-Casterman etc. first reported the existence of a natural heavy chain antibody (HCAbs) lacking of light chain in camel blood. The variable region of the natural heavy chain antibody separately forms a complete antigen binding sites, whose scale is nanoscale, so the antibody is also known as the nanobody (Nbs). Study result shows that said antibody has lots of peculiar properties such as excellent stability, high affinity, weak immunogenicity, strong tissues penetration and so on superior to ordinary antibodies. Therefore, it has a vast potential for future development in the field of medicine.
Existing research shows that using type II pneumonocyte as a target could carry out targeting transportation of lung tissue drugs. Type II pneumonocyte is exclusively contained in lung tissues, and it is one sort of cell which has the function of proliferation and secretion, its amount is about 16% of the total lung parenchymal cells, with the function of synthesizing and secreting pulmonary surfactants. The pulmonary surfactants, which are composed primarily of lipids (90%) and proteins (10%), are stored in the lamellar body within a cell, then said pulmonary surfactants could be secreted in alveolar spaces for producing physiological effects. The protein component in the pulmonary surfactant is the specific surfactant protein (SP), which is named SP-A, SP-B, SP-C, SP-D according to the order it is discovered. Wherein, SP-A is a hydrophilic glycoprotein, consisting of 248 amino acids, and SP-A is the earliest protein with a strong signal and being strongly expressed in type H pneumonocyte found by human being. The study found that, it could keep a high concentration of SP-A expression in lung and an extremely low concentration of SP-A extrapulmonary expression, so SP-A has lung specificity and becomes an ideal lung-specific targeting molecule. In conclusion, it is achievable that glucocorticoids are targeting transported to human lung tissues as long as the specific nano-drug carriers are loaded with glucocorticoids and then are coupled with nanobodies against human pulmonary surfactant protein A.
The applicant has successfully developed a rat pulmonary targeting immune liposome of methylprednisolone previously (Application Number: CN201510334884.9). It possesses definite rat pulmonary targeting and efficiently and stably carries out targeting transportation of active pharmaceutical ingredient to rat lung tissues. The lung tissue targeting ligand used in the invention is the murine SP-A nanobody (SPANb) self-developed by present R&D team (Application Number: CN201310134673.1). Recently, present R&D team further has successfully developed the humanized SP-A nanobody (Application Number: CN201510086499.7). Based on above studies made by present R&D team, this invention successfully provides a new human lung tissues targeting hormone preparation, with the final purpose of maximizing drug therapeutic effect while minimizing the adverse drug reaction by clinically using this new preparation, with high efficiency and low toxicity, in the treatment of human pulmonary diseases.